title: Acute depletion of endothelial β3-integrin transiently inhibits tumor growth and angiogenesis in mice.
abstract: BACKGROUND
  The dramatic upregulation of αvβ3-integrin that occurs in the vasculature during tumor growth has long suggested that the endothelial expression of this molecule is an ideal target for antiangiogenic therapy to treat cancer. This discovery led to the development of small-molecule inhibitors directed against αvβ3-integrin that are currently in clinical trials. In 2002, we reported that β3-integrin-knockout mice exhibit enhanced tumor growth and angiogenesis. However, as β3-integrin is expressed by a wide variety of cells, endothelial cell-specific contributions to tumor angiogenesis are muddied by the use of a global knockout of β3-integrin function.
  
  
  OBJECTIVE
  Our aim was to examine the endothelial-specific contribution β3-integrin makes to tumor growth and angiogenesis.
  
  
  RESULTS
  We have crossed β3-integrin-floxed (β3-floxed) mice to 2 endothelial-specific Cre models and examined angiogenic responses in vivo, ex vivo, and in vitro. We show that acute depletion of endothelial β3-integrin inhibits tumor growth and angiogenesis preventatively, but not in already established tumors. However, the effects are transient, and long-term depletion of the molecule is ineffective. Furthermore, long-term depletion of the molecule correlates with many molecular changes, such as reduced levels of focal adhesion kinase expression and a misbalance in focal adhesion kinase phosphorylation, which may lead to a release from the inhibitory effects of decreased endothelial β3-integrin expression.
  
  
  CONCLUSIONS
  Our findings imply that timing and length of inhibition are critical factors that need to be considered when targeting the endothelial expression of β3-integrin to inhibit tumor growth and angiogenesis.
authors.affiliation: From the School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich, United Kingdom (V.S., T.S.E., A.M.G., D.E., S.D.R.); Department of Internal Medicine, Division of Molecular Oncology, Washington University in St Louis, MO (K.W.); Luxembourg Center for Systems Biomedicine, University of Luxembourg, Luxembourg and Saarland University Medical Center, Internal Medicine II, Homburg, Germany (J.G.S.); UCL Institute of Ophthalmology, University College London, London, United Kingdom (M.F.); Barts Cancer Institute - a Cancer Research UK Centre of Excellence, Queen Mary, University of London, John Vane Science Centre, Charterhouse Square, London, United Kingdom (K.M.H.-D.).
authors.forename: Veronica
authors.initials: V
authors.lastname: Steri
authors.forename: Tim S
authors.initials: TS
authors.lastname: Ellison
authors.forename: Aleksander Maksym
authors.initials: AM
authors.lastname: Gontarczyk
authors.forename: Katherine
authors.initials: K
authors.lastname: Weilbaecher
authors.forename: Jochen G
authors.initials: JG
authors.lastname: Schneider
authors.forename: Dylan
authors.initials: D
authors.lastname: Edwards
authors.forename: Marcus
authors.initials: M
authors.lastname: Fruttiger
authors.forename: Kairbaan M
authors.initials: KM
authors.lastname: Hodivala-Dilke
authors.forename: Stephen Douglas
authors.initials: SD
authors.lastname: Robinson
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D039302:Integrin alphaVbeta3 / Q000235:genetics* / Q000378:metabolism; D008168:Lung / Q000098:blood supply / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000473:pathology
chemical_list: D039302:Integrin alphaVbeta3; D051416:Focal Adhesion Protein-Tyrosine Kinases
keywords: angiogenesis inhibitors; endothelium; integrin αVβ3; neoplasms